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  • EXPRESSION  (57)
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  • 1
    Keywords: E ; TOCOPHEROL ; VITAMIN-E ; ALPHA-TOCOPHEROL ; CD95 ; LIGAND ; EXPRESSION ; CD95 ligand ; ALPHA
    Type of Publication: Book chapter
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; PATHWAY ; PATHWAYS ; VITRO ; SYSTEM ; DEATH ; DISTINCT ; TIME ; COMPLEX ; COMPLEXES ; primary ; T cell ; T cells ; T-CELL ; T-CELLS ; culture ; activation-induced cell death ; CELL-DEATH ; UP-REGULATION ; CYCLE PROGRESSION ; DISPLAY ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; B-CELLS ; immune response ; IMMUNE-RESPONSE ; IL-2 ; INITIATION ; FAS-MEDIATED APOPTOSIS ; DISC ; SIGNALING COMPLEX ; ANTIGEN RECEPTOR ; C-FLIPSHORT ; CD95 ; COMPLEX DISC ; FLICE-INHIBITORY PROTEIN ; INTERLEUKIN-2 RECEPTOR
    Abstract: The CD95 (APO-1/Fas) system plays a critical role in activation-induced cell death (AICD) of T cells. We previously described two distinct CD95 (APO-1/Fas) signaling pathways: 1) type I cells show strong death-inducing signaling complex (DISC) formation and mitochondria-independent apoptosis and 2) DISC formation is reduced in type II cells, leading to mitochondria-dependent apoptosis. To investigate the relevance of these pathways, we set up an in vitro model that mimics the initiation and the down phase of an immune response, respectively. Freshly activated human T cells (initiation) are resistant toward CD95-mediated AICD despite high expression of CD95. We previously reported that these T cells show reduced DISC formation. In this study, we show that freshly activated T cells are CD95-type II cells that show high expression levels of Bcl-x(L) and display a block in the mitochondrial apoptosis pathway. Furthermore, we show that, upon prolonged culture (down phase), human T cells undergo a switch from type II to type I cells that renders T cells sensitive to CD95-mediated AICD. Finally, we demonstrate that this switch is dependent on the presence of IL-2. Our observations reveal for the first time that the existence of coexisting CD95 signaling pathways is of physiological relevance
    Type of Publication: Journal article published
    PubMed ID: 12960316
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  • 3
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; INHIBITOR ; tumor ; KINASE ; DEATH ; PROTEIN ; MONOCLONAL-ANTIBODY ; DEATH DOMAIN ; TUMOR-NECROSIS-FACTOR ; COMPLEX ; LIGAND ; COMPLEXES ; DOMAIN ; mechanisms ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; treatment ; antibodies ; antibody ; INDUCED APOPTOSIS ; MODULATION ; PATHOGENESIS ; DISC ; SIGNALING COMPLEX ; ANTI-APOPTOTIC MOLECULE ; CASPASE-8 ACTIVATION ; DEATH-EFFECTOR DOMAIN ; FAS/TNFR1- INDUCED APOPTOSIS ; INHIBITORY PROTEIN ; INTEGRIN ACTIVATION ; INTRACELLULAR REGULATION ; SURFACE ANTIGEN
    Abstract: Fas, upon cross-linking with Fas ligand (FasL) or Fas agonistic antibody, transduces apoptotic yet also proliferative signals, which have been implicated in tumor pathogenesis. In this study, we investigated the molecular mechanisms that control Fas-mediated signaling in glioma cells. Fas agonistic antibody, CH-11, induced apoptosis in sensitive glioma cells through caspase-8 recruitment to the Fas-mediated death-inducing signaling complex (DISC) where caspase-8 was cleaved to initiate apoptosis through a systematic cleavage of downstream substrates. In contrast, CH-11 stimulated cell growth in resistant glioma cells through recruitment of c-FLIP (cellular Fas-associated death domain (FADD)-like interleukin-1beta- converting enzyme (FLICE)-inhibitory protein) to the Fas- mediated DISC. Three isoforms of long form c-FLIP were detected in glioma cells, but only the phosphorylated isoform was recruited to and cleaved into a p43 intermediate form in the Fas-mediated DISC in resistant cells. Calcium/calmodulin- dependent protein kinase II (CaMK II) activity was up-regulated in resistant cells. Treatment of resistant cells with the CaMK II inhibitor KN-93 inhibited CaMK II activity, reduced c-FLIP expression, inhibited c-FLIP phosphorylation, and rescued CH-11 sensitivity. Transfection of CaMK II cDNA in sensitive cells rendered them resistant to CH-11. These results indicated that CaMK 11 regulates c-FLIP expression and phosphorylation, thus modulating Fas-mediated signaling in glioma cells
    Type of Publication: Journal article published
    PubMed ID: 12496285
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  • 4
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; INHIBITION ; VIVO ; DISEASE ; SITE ; SITES ; GENE ; transcription ; DIFFERENTIATION ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; TRANSCRIPTION FACTOR ; AP-1 ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; PROMOTER ; BETA ; immune response ; IMMUNE-RESPONSE ; LIVING CELLS ; CD28 ; C-REL ; T lymphocyte,transcription factor,cytokine
    Abstract: IL-4 plays a pivotal role in the development of the Th2 cell mediated humoral immune response and causes IgE-dependent allergic inflammatory diseases. Expression of IL-4 in differentiated Th2 cells is regulated by transcription factors such as NF-AT AP-1 and NF-IL6. Recently, increasing evidence indicates that the pro-inflammatory transcription factor NF-kappaB,13 may also participate in IL-4 expression. In this study, we show that the IL-4 promoter is synergistically activated by NF-kappaB, NF-AT and NF-IL6 at the NF-kappaB/NF-AT/NF-IL6 composite sites. In addition, we performed the chromatin immunoprecipitation technique to determine the functional relevance of NF-kappaB in the activation of the IL-4 gene in vivo. We demonstrate that NF-kappaB binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappaB nuclear translocation in living cells blocked binding of NF-kappaB to the IL-4 promoter. The data provide first evidence that NF-kappaB is directly involved in IL-4 transcription
    Type of Publication: Journal article published
    PubMed ID: 15048722
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  • 5
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; DEATH ; PROTEIN ; PROTEINS ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; primary ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; DOWN-REGULATION ; culture ; IMMUNE-RESPONSES ; resistance ; CELL-DEATH ; UP-REGULATION ; immune response ; IMMUNE-RESPONSE ; CASPASE 8 ; FAS-MEDIATED APOPTOSIS ; SIGNALING COMPLEX ; EFFECTOR ; Bcl-2 ; FLICE-INHIBITORY PROTEIN ; CASPASE-8 ACTIVATION ; ACQUIRE
    Abstract: In the early phase of an immune response, T cells are activated and acquire effector functions. Whereas these short term activated T cells are resistant to CD95-mediated apoptosis, activated T cells in prolonged culture are readily sensitive, leading to activation-induced cell death and termination of the immune response. The translation inhibitor, cycloheximide, partially overcomes the apoptosis resistance of short term activated primary human T cells. Using this model we show in this study that sensitization of T cells to apoptosis occurs upstream of mitochondria. Neither death-inducing signaling complex formation nor expression of Bcl-2 proteins is altered in sensitized T cells. Although the caspase-8 inhibitor c-FLIPlong was only slightly down-regulated in sensitized T cells, c-FLIPshort became almost undetectable. This correlated with caspase-8 activation and apoptosis. These data suggest that c-FLIPshort, rather than c-FLIPlong, confers resistance of T cells to CD95-mediated apoptosis in the context of immune responses
    Type of Publication: Journal article published
    PubMed ID: 14764686
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  • 6
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; DEATH ; GENE ; PROTEIN ; RNA ; LINES ; gene transfer ; GENE-TRANSFER ; MECHANISM ; RAT ; CONTRAST ; mechanisms ; CELL-LINES ; PROTEIN-KINASE ; CLEAVAGE ; resistance ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; MEMBRANE ; LINE ; KAPPA-B ; sensitivity ; OVEREXPRESSION ; cell lines ; CASPASE-8 CLEAVAGE ; SIGNALING COMPLEX ; CASPASE ; INHIBITORS ; RE ; GLIOMA ; CASPASE-8 ; OLIGONUCLEOTIDE ; NEURONS ; C-FLIP ; cell death ; ANTISENSE OLIGONUCLEOTIDE ; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME ; CEREBELLAR GRANULE NEURONS ; Fas/CD95 ; IMMUNE PRIVILEGE ; lifeguard ; PHOSPHATIDYLINOSITOL 3-KINASE ; PI3-kinase/ Akt
    Abstract: The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI3-kinase, overexpression of the inhibitory protein I kappa B, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e. g., inhibition of the PI3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL
    Type of Publication: Journal article published
    PubMed ID: 16033886
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  • 7
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; Germany ; DEATH ; PROTEIN ; PROTEINS ; LINES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; T-CELLS ; CELL-LINES ; VARIANTS ; UP-REGULATION ; NUMBER ; LINE ; cell lines ; REGULATOR ; SIGNALING COMPLEX DISC ; SIGNALING COMPLEX ; EFFECTOR ; CD95 APO-1/FAS ; CD95 ; HUMAN T-CELLS ; PROGRAM ; RE ; CASPASE-8 ; MEDIATED APOPTOSIS ; regulation ; CD95-MEDIATED APOPTOSIS ; SIGNALING COMPLEXES ; FLICE-INHIBITORY PROTEINS
    Abstract: c-FLIPs (c-FLICE inhibitory proteins) play an essential role in regulation of death receptor-induced apoptosis. Multiple splice variants of c-FLIP have been described on the mRNA level; so far only two of them, c-FLIPL and c-FLIPS, had been found to be expressed at the protein level. In this report, we reveal the endogenous expression of a third isoform of c-FLIP. We demonstrate its presence in a number of T and B cell lines as well as in primary human T cells. We identified this isoform as c-FLIPR, a death effector domain-only splice variant previously identified on the mRNA level. Importantly, c-FLIPR is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex upon CD95 stimulation. Several properties of c-FLIPR are similar to c-FLIPS: both isoforms have a short half-life, a similar pattern of expression during activation of primary human T cells, and are strongly induced in T cells upon CD3/CD28 costimulation. Taken together, our data demonstrate endogenous expression of c-FLIPR and similar roles of c-FLIPR and c-FLIPS isoforms in death receptor-mediated apoptosis
    Type of Publication: Journal article published
    PubMed ID: 15701649
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  • 8
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; CELL ; Germany ; VITRO ; DEATH ; PATIENT ; MECHANISM ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; SUSCEPTIBILITY ; CD95 ligand ; CELL-DEATH ; LYMPHOCYTES ; INDIVIDUALS ; sensitivity ; MULTIPLE-SCLEROSIS ; GUIDELINES ; CD95 ; AUTOIMMUNE ENCEPHALOMYELITIS ; PROGRAM ; COSTIMULATION ; CD95-MEDIATED APOPTOSIS ; multiple sclerosis ; function ; DEFECT ; regulatory T cells ; EXPANSION ; regulatory T cell ; healthy individuals ; auto immunity ; DIAGNOSTIC-CRITERIA
    Abstract: Impaired suppressive function of CD4(+)CD25(high) regulatory T cells (T-reg) has been reported as a novel pathogenetic mechanism in Multiple sclerosis (MS). We addressed if high apoptosis sensitivity of MS-T-reg could explain this functional T-reg defect. T-reg from treatmentnaive MS patients showed high sensitivity towards CD95Ligand-mediated apoptosis and exhibited enhanced cell death to IL-2 and TCR-signal deprivation. Since susceptibility of T-reg to cell death was similar in MS patients and healthy controls, this cannot explain the inhibitory dysfunction of T-reg associated with MS. Furthermore, as cell death is not enhanced, therapeutic expansion of MS-T-reg in vitro should be a reasonable and novel therapeutic option. (c) 2006 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17092518
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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; INHIBITION ; PATHWAY ; PATHWAYS ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEINS ; RNA ; DRUG ; MONOCLONAL-ANTIBODY ; TUMORS ; RELEASE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; MECHANISM ; FAMILY ; DOMAIN ; INDUCTION ; mechanisms ; DOWN-REGULATION ; CYTOCHROME-C ; MITOCHONDRIA ; UNITED-STATES ; RECEPTORS ; OVEREXPRESSION ; TUMOR CELLS ; Bcl-2 ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CD95 ; CASPASE ; INHIBITORS ; signaling ; FAMILIES ; SOLID TUMORS ; CYCLOOXYGENASE-2 ; TUMOR-CELL ; death receptor ; downregulation ; function ; caspases ; DRUGS ; cyclooxygenase ; RELEVANCE ; NECROSIS ; MCL-1 ; CELECOXIB-INDUCED APOPTOSIS ; PRIMARY HUMAN HEPATOCYTES
    Abstract: Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNIF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cc leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release front mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small - interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria
    Type of Publication: Journal article published
    PubMed ID: 16849551
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  • 10
    Keywords: CELLS ; EXPRESSION ; IRRADIATION ; tumor ; CELL ; COMBINATION ; Germany ; DISEASE ; EXPOSURE ; TISSUE ; PATIENT ; NITRIC-OXIDE SYNTHASE ; NITRIC-OXIDE ; MECHANISM ; IMPACT ; mechanisms ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; FIELD ; LESIONS ; UP-REGULATION ; DAMAGE ; RECRUITMENT ; CLEARANCE ; FUTURE ; inflammation ; PROGRAM ; RE ; SYNTHASE ; chemokines ; REGULATORY T-CELLS ; SUBTYPES ; APOPTOTIC CELLS ; TESTS ; EVENTS ; SLE ; function ; nitric oxide ; regulatory T cells ; regulatory T cell ; PROTECTS ; CD4(+)CD25(+) ; ENVIRONMENTAL-FACTORS ; SKIN-LESIONS ; LUPUS-ERYTHEMATOSUS
    Abstract: The pathophysiology of cutaneous lupus erythematosus (CLE) has been investigated in numerous studies demonstrating that the combination of specific cellular and molecular events is leading to inflammation and tissue damage in this disease. However, a complete understanding of the diverse pathophysiological mechanisms and interactions does not exist. Various environmental factors influence the clinical expression of CLE and a striking relationship has emerged between sunlight exposure and the various subtypes of this disease. In the past years, photoprovocation tests with different ultraviolet (UV) wavelengths have been approved to be an optimal way to evaluate photosensitivity in patients with CLE. Furthermore, research on the pathogenetic mechanisms of UV-induced skin lesions has become an increasingly dynamic field and several new aspects of this disease could be identified. In this review, the impact of UV exposure that contributes to the manifestations of CLE is discussed and recently reported mechanisms in the pathophysiology of this disease are considered including the clearance of apoptotic cells, expression of inducible nitric oxide synthase, function of CD4(+)CD25(+) regulatory T cells, and the role of chemokines for lymphocyte recruitment. Elucidation of the relevant factors might lead to future development of effective strategies to prevent abnormal reactivity in patients with CLE
    Type of Publication: Journal article published
    PubMed ID: 16987823
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